New Study Supports Link Between Oral Pain Reliever Diclofenac and Cardiovascular Risks

Diclofenac belongs to a drug family known as nonsteroidal anti-inflammatory drugs (NSAIDs). It is available in the U.S. by prescription only in oral (CAMBIA, ZIPSOR, ZORVOLEX) and topical (FLECTOR, PENNSAID, SOLARAZE, VOLTAREN) forms. The drug is commonly available in over-the-counter forms in other countries. Diclofenac is the only NSAID that also is approved by the Food and Drug Administration (FDA) for topical use.[1]

With the exception of CAMBIA (which is approved by the FDA to treat acute migraine attacks in adults),[2] oral forms of diclofenac are approved to treat mild-to-moderate pain of any cause or pain associated with osteoarthritis, the most common form of arthritis that is characterized by pain and morning stiffness due to gradual deterioration of cartilage in bone joints.[3],[4],[5] The topical (gel, patch and solution) forms of diclofenac are approved to treat acute pain due to minor strains or sprains, osteoarthritis in the knees or hands, or actinic keratosis (scaly skin patches caused by years of sun exposure).[6],[7],[8],[9]

A 2013 study that examined prescription data from around the globe showed that oral diclofenac is the most commonly used NSAID in low-, middle- and high-income countries.[10] The same study also analyzed data from randomized clinical trials and controlled observational studies that compared different NSAIDs and showed that the cardiovascular risk profile of this drug is disturbingly similar to that of rofecoxib (VIOXX), a drug that was withdrawn from the global market due to its cardiovascular toxicity.

Due to that study, Public Citizen's Health Research Group has classified the oral forms of diclofenac as Do Not Use.[11] However, we continue to classify the topical forms as Limited Use[12] because they are an effective alternative to oral NSAIDs for treating hand or knee (but not hip joint) osteoarthritic pain.[13] Furthermore, levels of diclofenac in the blood with topical use are about 10 times lower than similar dosing with the oral forms.

A recent large, well-designed observational Danish study[14] provides further evidence regarding the cardiovascular risks of oral diclofenac. The study showed that diclofenac initiation was associated with a higher risk of major adverse cardiovascular events within 30 days of starting the drug compared with initiation of two other NSAIDs and the common non-NSAID painkiller acetaminophen (TYLENOL) and compared with not using any of these drugs. The study was published online in The BMJ, previously known as the British Medical Journal, on Sept. 4, 2018.

The Danish study[15]

Using national Danish databases, the study researchers identified four groups of adults who had complete medication (including both prescription and over-the-counter drugs that were dispensed at pharmacies) and medical information for at least thirteen consecutive months from January 1996 to December 2016. In total, there were about 1.4 million initiators of diclofenac (patients who had not received the drug from a pharmacy in the prior 12 months), 4.2 million initiators of two other NSAIDs (either ibuprofen [ADVIL, IBU-TAB, MOTRIN IB, PROFEN] or naproxen [ALEVE, ANAPROX DS, NAPRELAN, NAPROSYN]), 800,000 initiators of acetaminophen and 1.3 million nonusers (patients who had not received any of the aforementioned medications from a pharmacy during the prior 12 months). Patients in the last two groups matched those in the diclofenac group in terms of age, gender, medical conditions and other factors.

The researchers then examined how many patients in each group suffered a major adverse cardiovascular event within 30 days after receiving one of the drugs of interest or after being identified as a nonuser. Major adverse cardiovascular events included any of the following outcomes: atrial fibrillation or flutter (two types of abnormal heart rhythms), ischemic stroke (stroke due to a blocked artery in the brain), heart failure, heart attack or heartrelated death.

The study showed that the rate of major adverse cardiovascular events was 20 percent higher among diclofenac initiators than among ibuprofen or acetaminophen initiators. The rate of these events among diclofenac initiators also was 30 percent and 50 percent higher than among naproxen initiators and nonusers of any of these drugs, respectively.

Notably, the researchers found that the increased cardiovascular risks among diclofenac initiators compared with the other patient groups were consistent among men and women of all ages. Likewise, the increased cardiovascular risks were seen with both low doses (less than 100 milligrams [mg]) and high doses (100 mg or higher) of diclofenac.

This study thus showed that the increased cardiovascular risks of diclofenac were apparent within just 30 days of use, even with low doses.

Consistent with prior research, the study also showed that initiation of diclofenac increased the risk of upper gastrointestinal bleeding within 30 days by approximately 2.5-fold compared with the initiation of ibuprofen or acetaminophen and by 4.5-fold compared with not using any of these drugs. However, diclofenac and naproxen initiation were associated with a similar risk of upper gastrointestinal bleeding.

The study researchers concluded that using NSAIDs to relieve pain or treat inflammation may be worthwhile for some patients to improve quality of life despite potential adverse effects. However, they emphasized that there is little justification to use diclofenac before other NSAIDs. They called upon health care professionals to acknowledge the health risks of diclofenac and to reduce its use.

What You Can Do

Do not use oral diclofenac for any purpose given its risks of major cardiovascular events and upper gastrointestinal bleeding. If you experience pain or have osteoarthritis that requires drug treatment, opt for acetaminophen, ibuprofen or naproxen because the safety profiles of these drugs are better than that of diclofenac. Use the lowest possible dose of ibuprofen and naproxen for the shortest possible duration to avoid adverse effects.

References

[1] Eight treatments commonly used for osteoarthritis pain. Worst Pills, Best Pills News. July 2015. /newsletters/view/975##ref_10. Accessed December 4, 2018.

[2] Depomed, Inc. Label: diclofenac (CAMBIA). November 2017. https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=d249ced1-4ca0-4f57-adcb-23440f58f659. Accessed December 4, 2018.

[3] G.D. Searle LLC Division of Pfizer Inc. Label: diclofenac (ARTHROTEC). August 2017. https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=600fe842-45d9-4d68-9ef2-456dbbebaa11. Accessed December 4, 2018.

[4] Depomed, Inc. Label: diclofenac (ZIPSOR). December 2017. https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=c982eca0-fc41-11e1-a9c8-0002a5d5c51b. Accessed December 4, 2018.

[5] Iroko Pharmaceuticals LLC. Label: diclofenac (ZORVOLEX). May 2016. https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=dff10e66-a577-451d-ba75-1889458ca833. Accessed December 4, 2018.

[6] Pfizer, Inc. Label. Diclofenac epolamine patch (FLECTOR). September 2018. https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=f103f7e8-1253-43cb-9667-cd0d8f4d5500. Accessed December 4, 2018.

[7] Horizon Pharma Inc. Label: diclofenac sodium (PENNSAID). May 2016. https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=802cd382-443d-48e3-9c9d-fd946c73c79f. Accessed December 4, 2018.

[8] PharmaDerm a division of Fougera Pharmaceuticals Inc. Label: diclofenac sodium gel (SOLARAZE). April 2016. https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=89a7bfbd-051f-4d87-a642-96b0df81b8e2. Accessed December 4, 2018.

[9] Endo Pharmaceuticals Inc. Label: diclofenac sodium gel (VOLTAREN). September 2018. https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=60045fc6-f0d9-4f67-ba91-c3b317596437. Accessed December 4, 2018.

[10] McGettigan P, Henry D. Use of non-steroidal anti-inflammatory drugs that elevate cardiovascular risk: an examination of sales and essential medicines lists in low-, middle-, and high-income countries. PLoS Med. 2013;10(2):e1001388.

[11] Further evidence that CELEBREX is a Do Not Use drug; new designation of diclofenac (VOLTAREN) as a Do Not Use drug; and other Do Not Use NSAIDS. June 2014. /newsletters/view/905. Accessed December 4, 2018.

[12] WorstPills.org. Drug profile: Non-steroidal anti-inflammatory drugs. August 2018. /monographs/view/117. Accessed December 4, 2018.

[13] Eight treatments commonly used for osteoarthritis pain. Worst Pills, Best Pills News. July 2015. /newsletters/view/975. Accessed December 4, 2018.

[14] Schmidt M, Sørensen HT, Pedersen L. Diclofenac use and cardiovascular risks: series of nationwide cohort studies. BMJ. 2018;362(Sep 4):k3426. doi:10.1136/bmj.k3426.

[15] Schmidt M, Sørensen HT, Pedersen L. Diclofenac use and cardiovascular risks: series of nationwide cohort studies. BMJ. 2018;362(Sep 4):k3426. doi:10.1136/bmj.k3426.